Normal adult hemoglobin comprises four globin proteins, two of which are .alpha. proteins and two of which are .beta. proteins. Diseases known as sickle cell syndromes are associated with disorders in the .beta. chain of the hemoglobin. However, in mammals, and particularly in humans, during fetal development, the fetus produces a fetal hemoglobin which comprises, instead of .beta.-globin proteins, two .gamma.-globin proteins. At some point during fetal development or infancy, depending on the particular species and individual, there is a so-called globin switch wherein the erythrocytes in the fetus switch from making predominantly .gamma.-globin to making predominantly .beta.-globin. It has been observed, however, that increased levels of fetal hemoglobin (derived from .gamma.-globin) ameliorate the severity of sickling disorders. It has also been observed that subjects heterozygous for hereditary persistence of fetal hemoglobin syndromes (HPFH) and sickling hemoglobin (HbS) are clinically asymptomatic of sickle cell anemia. Also, infants with sickle cell anemia do not usually develop the symptoms of the disease until approximately four months of age when their fetal hemoglobin levels decrease. These observations suggest that a method for increasing the levels of fetal hemoglobin would be beneficial to patients with sickle cell syndromes.
It is thus an object of the present invention to provide a method for inhibiting or reversing the .gamma. to .beta.-globin switch in a fetus or infant to maintain increased fetal hemoglobin levels in those individuals with sickle cell syndromes.
Since inhibition of the .gamma. to .beta.-globin gene switch has been observed in infants of diabetic mothers (IDM), it appears that disturbances in normal metabolites in the bloodstream might disrupt a normally timed and fixed gene-switch. Two metabolites, insulin and butyric acid, have been observed as being elevated in infants of diabetic mothers. Some investigators have shown that factors in serum can effect the .gamma. to .beta.-globin switching, particularly around the time the switch occurs. There has been, however, heretofore no development of a non-toxic therapeutic method or natural agent to increase fetal hemoglobin in subjects with sickle cell disease.
It is thus another object of the present invention to provide an agent for maintaining a high level of .gamma. chain synthesis (thereby maintaining high fetal hemoglobin levels), without toxicity and long term side effects, by using a physiologic factor rather than a chemotherapeutic agent.